Activation of Ventral Tegmental Area Cells by the Bed Nucleus of the Stria Terminalis: A Novel Excitatory Amino Acid Input to Midbrain Dopamine Neurons

We examined the role of excitatory amino acids (EAAs) in the activation of midbrain dopaminergic (DA) neurons evoked by stimulation of the ventromedial and ventrolateral (subcommissural) bed nucleus of the stria terminalis (vBNST). Using anesthetized rats and extracellular recording techniques, we found that 84.8% of ventral tegmental area (VTA) DA neurons were activated synaptically by single-pulse electrical stimulation of the vBNST. In contrast, similar stimulation did not affect the activity of presumed GABA neurons in the VTA. Three characteristic responses were observed in VTA DA neurons: short latency activation (<25 msec; 55.1% of cells), long latency activation (>65 msec; 56% of cells), and inhibition (61.8% of cells, usually followed by long latency excitation). Microinfusion of antagonists of EAA receptors (3 mM kynurenic acid, 100 μM AP-5, or 50 μM CNQX) from a micropipette adjacent to the recording electrode significantly reduced both short and long latency activations evoked in DA neurons by vBNST stimulation. Specific responses were attenuated similarly by AP-5 alone, CNQX alone, or a cocktail of AP-5+CNQX, indicating that joint activation of NMDA plus non-NMDA receptors was required. Stimulation of the vBNST by local microinfusion of glutamate increased the firing and bursting activity of VTA DA neurons. Similar microinfusion of GABA decreased bursting of VTA DA neurons without altering their firing rate. Retrograde and anterograde labeling and antidromic activation of vBNST neurons by VTA stimulation confirmed a direct projection from the vBNST to the VTA. These results reveal that inputs from the vBNST exert a strong excitatory influence on VTA DA neurons mediated by both NMDA and non-NMDA receptors.